Department Of Human Genetics And Molecular Medicine
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Item Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease(Elsevier B.V., 2023-06-29T00:00:00) Bhatti, Jasvinder Singh; Kaur, Satinder; Mishra, Jayapriya; Dibbanti, Harikrishnareddy; Singh, Arti; Reddy, Arubala P.; Bhatti, Gurjit Kaur; Reddy, P. HemachandraAlzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid ? (A?) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with A? and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with A? and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology. � 2023Item Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes(Springer, 2023-05-11T00:00:00) Malayil, Rhuthuparna; Chhichholiya, Yogita; Vasudeva, Kanika; Singh, Harsh Vikram; Singh, Tashvinder; Singh, Sandeep; Munshi, AnjanaOncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of�tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known�drugs. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4(BioMed Central Ltd, 2021-11-27T00:00:00) Sharma, Praveen; Sharma, Vibhuti; Ahluwalia, Tarunveer Singh; Dogra, Nilambra; Kumar, Santosh; Singh, SandeepBackground and objectives: MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria. Methods and results: Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells. Conclusion: These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription. � 2021, The Author(s).Item Small regulatory molecules acting big in cancer: Potential role of mito-miRs in cancer(Bentham Science Publishers, 2019) Sharma P.; Bharat; Dogra N.; Singh S.MicroRNAs [miRNAs] are short, non-coding, single stranded RNA molecules regulating gene expression of their targets at the posttranscriptional level by either degrading mRNA or by inhibiting translation. Previously, miRNAs have been reported to be present inside the mitochondria and these miRNAs have been termed as mito-miRs. Origin of these mito-miRs may either be from mitochondrial genome or import from nucleus. The second class of mito-miRs makes it important to unravel the involvement of miRNAs in crosstalk between nucleus and mitochondria. Since miRNAs are involved in various physiological processes, their deregulation is often associated with disease progression, including cancer. The current review focuses on the involvement of miRNAs in different mitochondrial mediated processes. It also highlights the importance of exploring the interaction of miRNAs with mitochondrial genome, which may lead to the development of small regulatory RNA based therapeutic options.Item Potential Mitochondrial-Specific Function Of piRNAs(Central University of Punjab, 2018) Paul, Shouvik; Singh, SandeepPiwi-interacting RNAs (piRNAs) are (26-31 nt) small noncoding RNAs processed from their longer precursor transcripts with the help of Piwi proteins. There are more than 30,000 piRNA genes present in the human genome which now turns out to be emerging player in both homeostasis and diseases. Localization of piRNA and PIWI in the repeat region of the mammalian nuclear genome in germ cells has been reported, although localization and potential functional role of piRNA in the mammalian mitochondrial genome are largely unknown. We have taken 111 piRNA sequences found in the MCF-7 mitochondrial genome, which is obtained by NGS analysis for alignment study. Resulting piRNA have been aligned with DQ112870 North American Homo sapiens mitochondrion genome for studying post- transcriptional roles of piRNA.Item Generation of Rho-0 Cells using MDA-MB-231 Cell Line and Measurement of Drug Cytotoxicity(Central University of Punjab, 2018) Sharma, Bharti; Singh,SandeepThe ATP generation via Oxidative phosphorylation (OXPHOS) system located in the inner membrane of mitochondria, is regulated by the coordinated interaction between nucleus and mitochondria. In the same context, mitochondrial-depleted cell (Rho-0) can be a helpful approach to study the mitochondrial metabolism, mitochondrial role in various cellular processes such as apoptosis, mitochondrial role in various mitochondrial related disorders and cancer. To generate Rho-0 cells, EtBr mediated mtDNA depletion was done and verified by agarose gel electrophoresis. % cell viability, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production was measured after 24 hr treatment with 3 drugs, ?-amanitin, Doxorubicin and DCA in both parental MDA-MB-231 and Rho-0 cells. Reduced cell death and ROS production was observed in Rho-0 cells indicating the resistance against apoptosis in Rho-0 cells and demonstrating the possible role of mitochondria in intrinsic pathway of apoptosis. MMP was observed to be maintained in Rho-0 cells indicating the role of nuclear genome in the maintenance of MMP.Item Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies(Springer, 2014) Kaur, Navrattan; Sarkar, Bibekananda; Mittal, Sunil; Dhiman, Monisha; Taglialatela, Gulio; Perez-polo, Regino J.; Mantha, Anil K.Alzheimer’s disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (Aβ) in senile plaques and neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins. New findings suggest that oligomeric Aβ is a more toxic species than fibrillar Aβ relevant to AD pathology. Although the molecular mechanism(s) underlying the disease is not identified completely, various factors have been implicated in the development of AD. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD and recognise them as an early event in AD development. Ageing is considered the greatest risk factor for AD and is linked to oxidative stress which causes accumulation of somatic mutations in mitochondrial DNA (mtDNA) over time and leads to genome instability and mitochondrial dysfunction. Recent studies on AD patients and transgenic mouse models suggest that amyloid precursor protein (APP) and Aβ localise to mitochondria, interact with mitochondrial proteins, disrupt electron transport chain (ETC), increases reactive oxygen species (ROS) level, impair axonal mitochondrial trafficking, thus leading to synaptic damage and cognitive decline associated with AD. It is not known whether accumulation of Aβ is the cause or outcome of declining mitochondrial function in AD. In order to counteract oxidative stress and maintain genome integrity, various DNA repair pathways exist, base excision repair (BER) pathway being the predominant pathway for repairing oxidised base lesions in neuronal cells. APE1 is the central enzyme of the BER pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. Newer studies are revealing the role of APE1 in maintenance of mitochondrial genome repair and function. In this scenario, antioxidant-based therapy, which could reduce oxidative stress and modulate the activities of APE1, can serve as effective treatment providing neuroprotection in AD. This book chapter summarises some recent developments in understanding the pathogenesis of AD linking Aβ-induced oxidative stress, mitochondrial dysfunction, role of APE1 and phytochemicals toward AD therapeutics.